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VOL. 73 (2), 537-566, 2007 ECTO-NUCLEOTIDASES, MOLECULAR PROPERTIES...

INTRODUCTION

Nucleotides are amongst the most ubiquitous messenger
substances in the vertebrate body. Receptors for nucleotides are
expressed on the surface of essentially every cell and many cells
carry several types of nucleotide receptors (1). The concept of
purinergic signaling as we understand it today reaches back into the
1960ies with a number of basic discoveries made by Geoffrey
Burnstock in Melbourne (2). ATP was the first nucleotide whose
signaling function was discovered, but it was later shown that also
other nucleotides evoke cellular responses. These include ADP, UTP,
UDP, nucleotide sugars and NAD+ as well as a variety of dinucleoside
polyphosphates (3, 4). The concept of nucleotide receptors was
initially developed on pharmacological and physiological grounds
and subsequently corroborated by the molecular cloning and
heterologous expression of nucleotide receptors. Nucleotide receptors
(P2 receptors) function either as cation channels (P2X receptors) or
are G-protein-coupled (P2Y receptors) (1). ATP can be released from
cells via constitutive or regulated pathways (5). Extracellular
nucleotides are inactivated by hydrolysis via ecto-nucleotidases with
the respective nucleoside as the final hydrolysis product that can be
salvaged via specific transporters (6). In the case of adenosine,
additional cellular functions can be mediated by P1 receptors.
Diadenosine polyphosphates act on a variety of receptors, including
P1, P2X and P2Y receptors (7) and endogenous dinucleotide
receptors (8).

THE BEGINNING

ATP was first identified in muscle extracts in 1929 independently
by Karl Lohmann at the Kaiser Wilhelm Institute for Biology in
Berlin and by Cyrus Hartwell Fiske and Yellagaprada SubbaRow at
Harvard University (9) (Figure 1). At that time, this discovery evoked
rather little response and the role of ATP as a high energy compound
and its role in carbohydrate breakdown were only realized during
the years following. The same year witnessed the first publication of
a biological activity of AMP and adenosine (on the heart and
vasculature) (10). In 1934 J. H. Gillespie in Belfast demonstrated a

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